The A- and B-type nuclear lamins are members of the intermediate filament family of proteins and represent important structural elements of the nuclear envelope (NE). The NE functions as a selective barrier between the nucleus and cytoplasm. Mutations in the A-type lamin gene, LMNA, have been linked to a variety of human disorders, often referred to as laminopathies, that include autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), dilated cardiomyopathy, Dunnigan type familial lipodystrophy and Hutchinson Gilford progeria syndrome. An X-linked form of EDMD is caused by defects in another NE protein, emerin. Emerin is an integral protein of the inner nuclear membrane and is associated with the A-type lamins. Both the A-type lamins and emerin are widely expressed. It is therefore puzzling why defects in these proteins should give rise to such a bewildering array of diseases. Recent results have shown that disease- linked defects in both A-type lamins and emerin are associated with cytoskeletal changes resulting in reduced mechanical resilience of the cytoplasm in fibroblasts. We have recently defined a complex consisting of members of both the SUN and nesprin protein families that functions as a link between the NE and the cytokeleton. We have termed this the LINC complex (LInker of Nucleoskeleton and Cytoskeleton). The LINC complex is the only known connection between the A-type lamins and the cytoskeleton. We hypothesize that it is the LINC complex that mediates the cytoskeletal changes associated with mutation of the A-type lamin and emerin genes. In this way the LINC complex might have a key role in the etiology of EDMD and other laminopathies. By gaining an improved understanding of the molecular interactions involved in the development of these disorders we may be in a better position to devise novel drug- or gene-based therapeutic strategies. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: The A-type lamins are important components of he nuclear envelope (NE). Defects in the A-type lamin gene (LMNA) are linked to a variety of human diseases or laminopathies, which include muscular dystrophy, lipodystrophy and progeria. The goal of this proposal is to determine the mechanism by which lamin defects can cause such disorders and to test the notion that SUN and nesprin proteins of the NE are mediators of these lamin-linked pathologies. [unreadable] [unreadable] [unreadable]